title: Mice engrafted with human fetal thymic tissue and hematopoietic stem cells develop pathology resembling chronic graft-versus-host disease.
abstract: Chronic graft-versus-host disease (cGVHD) is a significant roadblock to long-term hematopoietic stem cell (HSC) transplantation success. Effective treatments for cGVHD have been difficult to develop, in part because of a paucity of animal models that recapitulate the multiorgan pathologies observed in clinical cGVHD. Here we present an analysis of the pathology that occurs in immunodeficient mice engrafted with human fetal HSCs and implanted with fragments of human fetal thymus and liver. Starting at time points generally later than 100 days post-transplantation, the mice developed signs of illness, including multiorgan cellular infiltrates containing human T cells, B cells, and macrophages; fibrosis in sites such as lungs and liver; and thickened skin with alopecia. Experimental manipulations that delayed or reduced the efficiency of the HSC engraftment did not affect the timing or progression of disease manifestations, suggesting that pathology in this model is driven more by factors associated with the engrafted human thymic organoid. Disease progression was typically accompanied by extensive fibrosis and degradation of the thymic organoid, and there was an inverse correlation of disease severity with the frequency of FoxP3(+) thymocytes. Hence, the human thymic tissue may contribute T cells with pathogenic potential, but the generation of regulatory T cells in the thymic organoid may help to control these cells before pathology resembling cGVHD eventually develops. This model thus provides a new system to investigate disease pathophysiology relating to human thymic events and to evaluate treatment strategies to combat multiorgan fibrotic pathology produced by human immune cells.
authors.affiliation: Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Lockridge
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.forename: Yusof A
authors.initials: YA
authors.lastname: Becker
authors.forename: Shidong
authors.initials: S
authors.lastname: Ma
authors.forename: Shannon C
authors.initials: SC
authors.lastname: Kenney
authors.forename: Peiman
authors.initials: P
authors.lastname: Hematti
authors.forename: Christian M
authors.initials: CM
authors.lastname: Capitini
authors.forename: William J
authors.initials: WJ
authors.lastname: Burlingham
authors.forename: Annette
authors.initials: A
authors.lastname: Gendron-Fitzpatrick
authors.forename: Jenny E
authors.initials: JE
authors.lastname: Gumperz
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D016332:Fetal Tissue Transplantation / Q000379:methods*; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000276:immunology* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D013950:Thymus Gland / Q000637:transplantation*; D014183:Transplantation, Heterologous
keywords: Chronic GVHD; Humanized mouse